Depression is a disorder that involves changes in coordinated networks of hundreds of genes across key brain circuits, according to a study conducted at the Icahn School of Medicine at Mount Sinai and published May 12 in the journal Neuron.

The Mount Sinai study focuses on identifying how groups of genes operate in functional clusters or ‘gene networks’ to control communication across distinct areas in the brain or ‘brain circuits’ that are changed in depression.

While previous research has suggested that multiple brain regions play a role in depression, how gene activity controls brain circuits has not been investigated. Most studies looked only at how the activity of individual genes is increased or decreased in isolated brain areas in depression without investigating how the relationship between groups of genes is regulated.

The current team identified large gene networks that are altered in depression-like states, focusing on three specific genes that were “master regulators” of the gene networks. None of these genes had previously been linked to depression. The team demonstrated that manipulating the master regulator genes that control these networks could make mice susceptible or resilient to chronic stress.

“Our study is the first to identify and validate the gene networks at play across brain circuits, showing that manipulating their activity alters the activity of brain cells and ultimately, depression behavior,” says Rosemary C. Bagot, PhD, a postdoctoral researcher in the Nestler Laboratory of Molecular Psychiatry at Mount Sinai. “By considering both activity of individual genes and the relationship between groups of genes in several brain regions, our team found that depression may reflect fundamental changes in the architecture of gene networks, rather than just simple increases or decreases in the activity of genes.”

Using a mouse model of human depression, the current research team systematically examined the multifaceted dysregulation of gene networks within several inter-connected brain regions implicated in depression: the nucleus accumbens (NAc); the prefrontal cortex; the amygdala and the ventral hippocampus.

The brain areas studied form a circuit with the NAc at its center, integrating diverse input from the other three regions to drive motivated behavior. The NAc receives information about executive control and attention from the prefrontal cortex; context, space and emotional data from the ventral hippocampus; and information about both learned associations and emotion from the amygdala.

Using RNA sequencing to create a complete picture of gene expression in these interconnected brain regions, the study team found a striking difference in patterns of gene expression between resilient and susceptible mice.

Specifically, researchers found an opposing relationship between the prefrontal cortex and the ventral hippocampus. By manipulating master regulators of key gene networks within each of these brain regions, they found a key role for the ventral hippocampus in making mice susceptible to depression, whereas the prefrontal cortex was important in making mice resilient.

“Our study is unique in that we took information about coordinated gene networks involved in depression and then actually went back and manipulated these networks within animals to conclusively show that the networks regulate depression-like behavior,” says Dr. Bagot.

The research team is now investigating how to target these gene networks with drugs to make mice that are prone to depression more resilient, as a strategy to discover novel, effective treatments for depression in humans.

“We don’t fully understand how current antidepressant drugs work and many patients don’t respond well to treatment,” says Eric Nestler, MD, PhD, Nash Family Professor of Neuroscience and Director of the Friedman Brain Institute at Mount Sinai. “The hope is that we can develop more effective treatments by first understanding what is actually happening in the brain in depression. This study’s findings suggest that we need drugs that can alter how clusters of genes function within brain circuits. Depression is a circuit-level disorder and needs to be understood and treated at that level.”

The study was led by Drs. Bagot and Nestler and two other senior investigators, Li Shen, PhD, and Bin Zhang, PhD, from the Icahn School of Medicine at Mount Sinai. The research team from Mount Sinai collaborated with researchers from the University of Pittsburgh; the University of California, Los Angeles; and the Massachusetts Institute of Technology.

The study was financially supported by P50 MH096890, the Hope for Depression Research Foundation (HDRF), a 2014 NARSAD Young Investigator Award 22713 from the Brain & Behavior Research Foundation, grant R01AG046170 from the National Institute on Aging, and grants U01AI111598-01 and K99 MH10237 from the National Institute of Allergy and Infectious Diseases.

The Mount Sinai Health System is an integrated health system committed to providing distinguished care, conducting transformative research, and advancing biomedical education. Structured around seven hospital campuses and a single medical school, the Health System has an extensive ambulatory network and a range of inpatient and outpatient services—from community-based facilities to tertiary and quaternary care.

The System includes approximately 7,100 primary and specialty care physicians; 12 joint-venture ambulatory surgery centers; more than 140 ambulatory practices throughout the five boroughs of New York City, Westchester, Long Island, and Florida; and 31 affiliated community health centers. Physicians are affiliated with the renowned Icahn School of Medicine at Mount Sinai, which is ranked among the highest in the nation in National Institutes of Health funding per investigator. The Mount Sinai Hospital is in the "Honor Roll" of best hospitals in America, ranked No. 15 nationally in the 2016-2017 "Best Hospitals" issue of U.S. News & World Report. The Mount Sinai Hospital is also ranked as one of the nation's top 20 hospitals in Geriatrics, Gastroenterology/GI Surgery, Cardiology/Heart Surgery, Diabetes/Endocrinology, Nephrology, Neurology/Neurosurgery, and Ear, Nose & Throat, and is in the top 50 in four other specialties. New York Eye and Ear Infirmary of Mount Sinai is ranked No. 10 nationally for Ophthalmology, while Mount Sinai Beth Israel, Mount Sinai St. Luke's, and Mount Sinai West are ranked regionally. Mount Sinai's Kravis Children's Hospital is ranked in seven out of ten pediatric specialties by U.S. News & World Report in "Best Children's Hospitals."